16-lower alkyl-17-alkynyltestosterones



United States Patent 3,010,959 16-LOWER ALKYL-17-ALKYNYL- V TESTOSTERONES Eugene P. Oliveto, Bloomfield, and Richard Rausser,

Union, N.J., assignors to Schering Corporation, Bloomfield, N.J., a corporation of New Jersey No Drawing. Filed Nov. 26, 1958, Ser. No. 776,447

6 Claims. (Cl. 260-23955) This invention relates to a new group of therapeutically active steroid compounds. More particularly, the invention relates to certain 17cz-filkYIlYl-16-1OWGI' alkylandrostadienes and intermediates leading thereto, and to methods for their manufacture.

The novel compounds of the present invention may be represented by the following formula:

Y M lower alkyl wherein X is a member of the group consisting of H and halogen having an atomic weight less than 100; Y is a member of the group consisting of 0 and (H, 50H); R is a member of the group consisting of H and lower alkyl, and the term lower alkyl stands for an on or ,8 alkyl group having up to four carbon atoms; and the 1,2- dihydro analogs thereof.

In the above formula and throughout the instant application, a bond designated as f signifies that the substituents attached to such a bond have either an a or ,8 configuration.

Valuable intermediates useful in the preparation of the above compounds are those having the formula and designation shown above except that X and Y together represent a 95,1lfl-oxido group.

The preferred final compounds of our invention are those wherein X is halogen and R is hydrogen, and in particular, 9a-fluoro-16-methyl-(m or B)-17u-ethinyl-1,4-androstadiene-l1,8,17/3-diol-3-one.

It has been found that the 1,4-diene compounds of this invention, especially the 9a-fluoro, are potent anti-inflammatory agents possessing a degree of catabolic and antianabolic activities. While being essentially free of androgenic and salt retaining effects, our compounds are indicated for use in conditions such as arthritis where antiinfiammatory and anti-anabolic agents have been employed and certain syndromes such as Pagets disease of bone.

The presence of the alkyl group, especially methyl, in the l6-position potentiates the activity of the substance and provides for a more favorable thereapeutic ratio. Similar anti-inflammatory properties are exhibited by the A -monoenes, however, their principal use is as intermediates for the manufacture of the more potent and advantageously employed 1,4-dienes.

The therapeutically active compounds are preferably administered orally in the form of tablets. For example,

a tablet composed of about to 50 mg. of 9nc-fiuOr0-16- (on or ;8)-methyl l7a-ethinyl-1,4-androstadiene-l1 8,175- diol-3-one in admixture with a mixed solid carrier containing one or more of the usual ingredients, such as starch, sugar, gums, clays and the like provides a usable pharmaceutical dosage form which can be administered 3 to4 times daily. Other dosage forms such as solutions, elixirs, and the like also lend themselves to such administration.

The therapeutically valuable compounds of our invention are prepared by a number of easily effected transformations. For example, in the manner described in our co-pending application, Serial No. 776,446, filed November 26, 1958, the 16-alkyl-17-keto-1,4-androstadienes are obtained by the oxidative degradation of an appropri ately substituted pregnadiene by means of sodium bismuthate. (The 16-alkyl-pregnadiene starting compounds are prepared according to the procedure described in copending application of Rausser et al., Serial No. 733,843 filed on May 8, 1958.) The 16-alkyl-17-keto-1,4-androstadienes are then alkynated in the conventional manner, such as with acetylene and potassium in anhydrous ether, or sodamide in liquid ammonia or lithium acetylide. In carrying out the alkynation, it is often desirable to protect the 3-keto group in the A-ring by the formation of a pyrrolidyl enamine or ethylene ketal derivative in order to increase yields and obtain purer products. Thus, the oxidation of 9a fluoro 16u-methyl-1,4-pregnadiene-l1B, l7a,21-triol-3,20-dione with sodium bismuthate in acetic acid yields 9oc-fill01'O-1 6u-methyl-1,4-androstadiene-1 1,8-01- 3,17-dione. Ethynation with potassium in anhydrous ether yields 91! fluoro-l6a-methyl-17a-ethinyl-1,4-androstadiene-l 1,B,17B-diol-3-one.

While the degradation of the C-21 steroids is customarily carried out in aqueous acetic acid, other water miscible fatty acids such as propionic acid can be used. Likewise, other oxidizing agents may be used in place of sodium bismuthate, such as lead tetraacetate, periodic acid or chromic acid. With chromic acid, however, an llfl-hydroxyl group, if present, will be oxidized to an 1l-ketone.'

In the foregoing process, the substitution of potassium methyl-acetylide (or other alkali metal methyl-acetylide) for potassium acetylide yields a 17a(methyl-ethinyl)-17[3- hydroxy-unsaturated androstane. Similarly, other potassium (or other alkali metal) alkyl-substituted' acetylides may be used in the above process for example, potassium ethyl-, propyl-, isopropyl-, butyl-, isobutyl-, and-tertiary butylacetylide, to yield the corresponding 17ot-alkylethinyl- 17/3-hydroxy-unsaturated androstane.

The oxidative degradation described above is also applicable to l6-alkylated-4-pregnenes whose preparation is described in the co-pending Rausser et a1. application supra. The A -bond can be introduced at any stage by means of any. of several methods known in the art. We prefer to employ microbiological dehydrogenation techniques such as use of Corynebacterium simplex described in U. S. Patent No. 2,837,464.

By our process, a 16-alkylated-4-pregnene such as l6a-methyl-cortisone when oxidized with sodium bismuthate yields 16a-methyl-4-androstene-3,1l,l7-trione. Reaction with acetylene in anhydrous ether in the presence of potassium yields l6a-methyl-17a-ethinyl 4 androstenel7/3-ol-3,11-dione. To obtain the corresponding 1,4-androstadiene, l6ot-methy1-l7a-ethinyl-4-androstene-17 3-01- 3,ll-dione is subjected to the action of a culture Corynebacterium simplex to give l6a-methyl-l7a-ethinyl-1,4-androstadienea17fl-ol-3Jl-dione. Alternatively, the diene may be obtained by dehydrogenating l6a-methyl-4-androstene-3,1l,17-trione by means of selenium dioxide for example, to give 16ot-methyl-1,4-androstadiene-3,l1,17-

' trione which is ethynated in the aforementioned manner to give the desired 1Got-methyl-l7u ethinyl-1,4-androstadicue-3 ,11,17-trione. I

Similarly, there may be obtained l6a-methyl-l7a-methylethinyl-4-androstene-l7/3-ol 3,11-dione from 16a-methylcortisone by first oxidizing the cortisone analog with sodium bismuthate to 16u-methyl-4-androstene-3,11,20- trione, which is then reacted with methylacetylene and potassium in ether to give 16a-methyl-l7a'methylethinyl- 4-androstene-17,B-ol-3,11-dione.

The oxidative degradation .is also applicable to nonhalogenated pregnene and pregnadiene precursors giving rise to a 16-alkyl-l,4-androstadiene-1l oxy-3,17-dione. In this instance, the 9a-halogeno group and the 17-alkynyl group can be sequentially introduced. We prefer to prepare the 9u-halogeno compounds of our invention from a 919,116-oxido precursor such as 16a-Inethyl-9fl,11 8-oxido- 1,4-androstadiene-3,l7-dione or its 1,2-dihydro analog. These oxido compounds are prepared as described in our co-pending application Serial No. 776,446, filed November 26, 1958, by the action of sodium bismuthate or chromic acid on a 16-a1kyl-9fi,1lB-oxido-l,4 pregnadiene- 17a,2'1-diol-3,20-dione. Alkynationof the 17-keto group as described heretofore, and opening the epoxide ring in the conventional manner gives rise to the novel halogenated compounds of this invention. For example, to obtain 9a-fiuoro-16a-methyl-17a-ethinyl-1,4-androstadiene, there is first prepared the appropriately substituted 95,11,8- oxido compound in the following manner. 16oc-methylhydrocortisone Zl-acetate is dehydrated by means of benzenesulfonyl chloride to give 16a-methyl-4,9-pregnadiene- 17a,21diol-3,20-dione 2l-acetate which is reacted with N-brornoacetamide and perchloric acid, for example, to give 9a-bromo-16tx-methylhydrocortisone 21-acetate. The 9a-bromo compound is refluxed in methanol in the presence of potassium acetate to obtain 9,8,11fi-oxido-l6umethyl-4-pregnene-17a,2l diol-3,20 dione 2l-acetate. Hydrolysis of the 9fl,1lB-oxido pregnene 2l-acetate to the 9,8,11,8-oxido pregnene 2l-a1cohol followed by the action of sodium bismuthate yields 95,1lfi-oxido-16a-methyl-4- androstene-3,l7-dione. The 9,9,115-oxido andros tene is converted to the corresponding l7-ethinyl compound by first forming a S-pyrrolidyl enamine and then ethinating and hydrolyzing'the 3-pyrrolidyl enamine to give 16ccmethyl-17a-ethinyl-9 5,1 lfi-oxidol-androstene 175-01-3- one. Upon reaction of the oxido compound with anhydrous hydrogen fluoride there is obtained 9ot-fiUOIO-l6amethyl l'lot-ethinyli androstene 115,175-diol-3-one which is dehydrogenated to the l-dehydro analog by the action of Cm-ynebacterium simplex.

Similarly, the 9a-chloro or 9a-brorno analogs of the above 4-androstene are obtained from 16a-methyl-17aethinyl-9,8,l lfi-oxido-4-androstene-1719-01-3-one by the action of anhydrous hydrogen chloride and anhydrous hydrogen bromide, respectively.

The following examples are illustrative of outinvention and are not to be construed as limiting the scope thereof.

EXAMPLE 1 16or-methyl-17a.-ethinyl-9fi,l1 ,8-oxido-4-androstene- 1 75-01-3 -one The requisite intermediates are prepared as follows:

A. 16st methyl-4,9-pregnadiene-1 70:,21 -dil-3,20-d1'0ne 21-acetate.To a solution of 16a-methylhydrocortisone ZI-acetate (0.3 g.), in ml. of pyridine there is added 0.2 ml. of benzenesulfonyl chloride in 3 ml. of pyridine. The solution is allowed to stand for 4 hours, then is poured into ice and hydrochloric acid. A solid precipitates which is filtered and crystallized from acetone-hexane to give 16m-methyl-4,9-pregnadiene171:,2l-diol-3,20- dione 2l-acetate,

A 239 my (616,020)

androstene l7fi-ol-3-one.

acetone to give 9a-bromo-16oz-methylhydrocortisone 21- acetate,

AMBOH max.

C. 9a-br0mo-16u-methylhydr0cortisone.-To 0.5 g. of 9a-bromo-l6ot-methylhydrocortisone ill-acetate in ml. of methanol and 20 ml. of chloroform there is added 5 m1. of water and 5 ml. of concentrated hydrochloric acid. The reaction mixture is allowed to stand 48 hours at room temperature at which time water is added, and the mixture extracted with methylene chloride. The organic extracts are combined, washed with Water, dried and concentrated to a residue. Crystallization of this residue from acetone yields 9a-bromo-16a-methylhydrocontisone.

D. 9 8,116 oxido 16ot-methyl-4-pregnene-17a,2J-di0l- 3,20-di0ne 21-acetate.To 9a-bromo-l6a-methylhydrocortisone Zlacetate of Example IE (0.3 g.), in 20 ml. of methanol there is added 0.3 g. of potassium acetate. The mixture is refluxed for 2 hours, then concentrated in vacuo to a residue. Water is added to the residue, and a solid separates which is filtered and crystallized from methanol-water to give 0.1 g. of 918,1lp-oxido-16a-methyl- 4-pregnene-l7a,21-diol-3,20-dione Zl-acetate.

E, 913,] 1 B-oxido-I out-m ethyl l-androstene-il 7-di0ne.-- A solution of 5.0 g. of 9,8,11fi-oxido-16a-methyl-4- pregnene-17a,2l-diol-3,20-dione 21-acetate in 20 ml. of methanol and 5 ml. of water containing 2.5 g. of sodium bicarbonate is refluxed for /2 hour. The methanol is removed by distillation and water added to precipitate 95,115 oxido 16a-methyl-4-pregnene-l7a,21-diol-3,20- dione. I

To 2 g. of the oxido-pregnene-Zl-ol prepared above in 200 ml. of acetic acid there is added 200 ml. of water containing 35 g. of sodium bismuthate, and the mixture is stirred overnight at room temperature. The solid is removed by filtration and washed with methylene chloride. The filtrate is further diluted with water and extracted with methylene chloride. The organic layer is washed neutral with sodium bicarbonate solution, then water, dried and evaporated to a residue. Crystallization of this residue from methanol-water gives 1.0 g. of 913,115- oxido-l6a-methyl-4-androstene-3,17-dione.

'F. 3 pyrrolidine-9,8,11,6-oxido-16ot-methyl-3,5-androstadiene17-0ne.--Three grams of the product of Example 11-3. is suspended in 10 ml. of methanol, and nitrogen bubbled through the mixture. The mixture is heated to boiling, then 1.0 g. of pyrrolidine is added and the heating continued until crystals appear (5-10 min). Upon cooling and filtering, 2.1 g. of 3-pyrrolidino-9,8,11fl-oxido-16amethyl-3,5-androstadiene-l7-one is obtained.

G. 16a methyl-l 7a-ethinyl-9;3,l1 p-oxidol-androstene- 17}8-0l-3-0ne.-A solution of 200 mg. of potassium in 20 m1. of redistilled t-amyl alcohol is added dropwise with stirring to a solution of 100 ml. of anhydrous ether saturated with acetylene. After five minutes of stirring, a solution of 1.5 g. of 3-pyrrolidino-9fi,llfl-oxido-lfiamethyl-3,S-androstadiene-l7-one in ml. of anhydrous other is added dropwise over 1 hour. Acetylene is bubbled through the stirred mixture during the addition of the oxido-androstadiene and this is continued for 2 hours longer. Dilute acetic acid is then added cautiously and the mixture boiled for 10 minutes, then extracted with ether. The ether solution is Washed to neutrality with sodium bicarbonate solution and water, dried and evaporated to a residue which is crystallized from acetonehexane to yield Met-methyl-17a-ethinyl-95,l1fi-oxido-4- The ethinyl compound of this example is also prepared from the oxido intermediate of Example 1E by ethinating directly as described in Example 1G.

Similarly, by starting with the lfi-methyl epimer and applying the foregoing procedure there is obtained 16;:- methyl 17a ethinyl-9B,11B-oxido-4-androstene-17fi-ol-3- A. 16a-methyl-4-andr0stene-11fi-0l-3,17-dione.-A solution of 3 g. of 16u-methylhydrocortisone in 300 ml. of acetic acid and 300 ml. of water containing 50 g. of sodium bismuthate is stirred at room temperature overnight. The undissolved solid is removed by filtration and washed with methylene chloride. The filtrate is further diluted with water and extracted with methylene chloride. The organic layer is separated and Washed neutral with sodium bicarbonate solution, then water, dried and evaporated to a residue. The residue is crystallized from methanol-water yielding 16a'-methyl-4-androstene-11,6-01- 3,17-dione.

B. 16a-methyl-17a-ezhinyl-4-androstene-11}3,1 7 fi-diOl-S- one.The 17-keto-androstene prepared as in Example 2A is reacted with acetylene as described in Example 1G, and the resultant product isolated and purified in the described manner to give 16u-methy1-l7u-ethinyl-4-androstene1 1,3,17,8-diol-3-one.

16B-methylhydrocortisone is reacted according to a procedure analogous to Example 2, and there is obtained 16fl-methyl-17a-ethinyl-4-androstene-1 15,175-dio1-3-one.

EXAMPLE 4 1 6a-metl1yl-1 7 a-ethinyl-4-androstene-1 7B-0l3,11-di0ne 16a-methylcortisone is oxidized according to the analogous procedure of Example 2 yielding 16a-methyl-4androstene-3,11,17-trione which is then ethinated as therein described to give 16a-methyl-17a-ethinyl-4-androstene- 17/8-o1-3,1l-dione Similarly, 16B-methyl-17a-ethinyl-4-androstene-175-01- 3,1l-dione is prepared from l6fi-methylcortisone.

EXAMPLE 1-6 a-methyl-I 7a-ethinyl-95J1B-oxid0-L4-androstadiene- 1 7/3-0l-3-0ne "Ihe 21-acetate of 16a-methylprednisolone, is subjected to the reaction sequence described in Example 1, to obtain 1Got-methyl-17a-ethinyl-1,4-androstadiene-17 3-0l-3-one.

Similarly, 16fi-methylprednisolone is converted by this procedure to 16,8 methyl 17a-ethinyl-9B,11 8-oxido-1,4- androstadiene-l7B-ol-3-one.

Alternatively, the 1,4-androstadienes and 1,4-pregnadienes of this example are prepared from the corresponding 4-androstenes and 4-pregnenes of Example 1 by introduction of a A -double bond at any point in the procedure by known chemical or microbiological procedui'es. Thus, subjecting 16-methyl(u or ,6)-17o..-ethiny1- 195,11B-oxido-4-androstene-17,8-ol-3-one to the microbiological dehydrogenating action of Corynebacterium simplex according to analogous procedures described in U.S. Patent No. 2,837,464 there is obtained the corresponding 1,4-androstadiene.

Alternatively, 9a-bromo-16a-methyl-hydrocortisone 21- acetate of Example 1B is converted by the action of Corynebacterium simplex to 9a-bromo-l6a-methylprednisolone ZI-acetate, which is then subjected to procedures analogous to Example 1D through 16 to give 16a-methyl- 17a-ethinyl-9p,11,B-oxido-1,4-androstadienes 175 01-3- one.

EXAMPLE 6 1 6 a-m ethyl 7 aethiny l-I ,4-androstad i an e- 11,8,1719-di0l-3-one A. 16a-methyl-1,4-androstadiene-1 16-01-51,] 7-di0ne. By substituting 16a-methylprednisolone for IGa-methylhydrocortisone in the procedure of Example 2A there is obtained 1oa-methyl-l,4-androstadiene-1lfi-ol-3,17-dione.

B. 16a-methyl-17a ethinyl 1,4 androstadiene 1113,

16a-methyl-1 7u-ethinyl-1,4-andr0stadiene- 1 7,8-0l-3,11-di0ne 16a-methylprednisone is reacted in the manner of Example 4 to give 16a-methyl-l7a-ethinyl-1,4-androstadicne-l7fl-ol-3,11-dione. In similar fashion, the 168- methyl epimer is obtained by subjecting 16,3-methy1- prednisone to the procedure of Example 4.

EXAMPLE 8 A solution of 0.1 g. of 16m-methyl-17a-ethinyl-9p,11poxido-4-androstene-17B-ol-3-one (obtained as in Example 1) in 5 ml. of alcohol-free chloroform is saturated with anhydrous hydrogen fluoride at 0 C. The mixture is allowed to stand for four hours at 0 C. and is then con cen-trated in vacuo to a residue. Crystallization of this residue from methanol water yields 75 mg. of 9a-fluoro- 16oc-methyl-17u-ethinyl-4-androstene 115,175 dio l 3- one.

EXAMPLE 9 9a-fluor0-16u-methyl-17a-ethinyl-1,4-androstadiene- 11;8,17p-di0l-3-0ne 16oz-methyl-17a-ethinyl-9B,1l 3-oxido 1,4 androstadiene-17;3-ol3-one (the compound of Example 5) is reacted with hydrogen fluoride in the manner of Example 8 to give 9a-fluoro-16u-methyl-17a-ethinyl-1,4androstadi ene-11fi,l7B-diol-3-one.

In similar fashion, 16,B-methyl 17u-ethinyl-9B,11,9 oxido-l,4-androstadierre-l7B-ol-3-one, prepared as described in Example 5, when reacted with hydrogen fluoride yields fluoro 16 9 methyl 17a-ethinyl-1,,4-androstadiene-l l [3, l7B-diol-3-one.

The dienes of this example are alternatively prepared by dehydrogenation of the A-ring. Thus, starting with the monoene of Example 1, namely, 16-methyl (a or 18)- 17u-ethinyl-9B,11fl-oxido-4-androstene-17p-ol-3-one, and subjecting same to the microbiological dehydrogenating activity of Corynebacterium simplex according to the procedure described in U.S. Patent No. 2,837,464, there is obtained the diene of this example, 90t-fluOI'O-16w' methyl-17a-ethinyl-4-androstene-1 1p,17e-dio1-3-one.

EXAMPLE 10 A solution of 0.2 g. of the 913,115-oxido compound of Example 1 in 10 ml. of alcohol-free chloroform is saturated with dry hydrogen chloride at 0 C. The mixture is maintained at 0 C. for four hours,-then evaporated to a residue. Upon crystallization of this residue from acetone-hexane there is obtained mg. of 9a chloro- 16a-methyl-17a-ethinyl-4-androstene 1119,17 3 diol-'3- one.

In similar fashion, by starting with the- IGfl-methyl epimer of the 95,11,8-oxido compound of Example 1, there is obtained 9a-chloro-1613-methyl-17a-ethinyl-4 androstene-l15,17,8-diol-3-one. I I

EXAMPLE '11;

9a-bromo-16m-methyl-1 7a-ethinyl-4-andr0stene- 11,3,17;8-di0l-3-0ne EXAMPLE 12 9a-chl0ro-16a-methy1-1 7e-ethinyl-1,4-andiostadiene- 1 1 ,1 7fi-diol-3-one The 16a-methyl-oxido-diene of Example 5 is subjected to the action of hydrogen chloride according to the procedure of Example to obtain 9uchloro-16a-methyl- 17u-ethinyl-1,4-androstadiene-1 15,17f3-diol-3-one.

' Alternatively, the dierie of this example may be prepared from the 9a-chloro-4-androstene of Example 10, by subjecting same to the microbiological dehydrogenating activity of Corynebacrerium simplex as described in US. Patent No. 2,837,464.

In similar fashion, 16p-methyl-l7u-ethinyl-9e,llfl-oxido-l,4-androstadiene-l75-01-3-one, prepared as described in Example 5, is reacted with hydrogen chloride according to the procedure of Example 10, to obtain 9a-ch1oro-16emethyl-l7u-ethinyl-1,4-androstadiene-1lfl,17fi-diol-3-one.

EXAMPLE 13 By subjecting the oxide compound of Example S to the action of hydrogen bromide as described in Example 11, there is obtained 9a-bromo-16a-methyl-17tx-ethinyl-1,4- androstadiene-l 15,17,8-diol-3-one.

Alternatively, the 9a-bromo-l,4-androstadiene of this example may be prepared by the action of Corynebacterium simplex on 9u-bromo-16a-methyl-l7a-ethinyl-4-androstene-11p,l7p-diol-3-one '(compound of Example 11) by procedures analogous to those described in U.S. Patent No. 2,837,464.

EXAMPLE l4 9a-fluoro-16u-methyl-1 7u-ethinyl-1 ,4-androstadiene- 1 73-016,! 1 -dione To 0.2 g. of 9a-fluoro-l6a-methyl-17u-ethinyl-1,4- androstadiene-I1,8,17p-diol-3-one (the compound of Example 9) dissolved in 10 ml. of acetic acid, there is added dropwise a solution of 40 g. of chromium trioxide in 1 ml. of water and 3 ml. of acetic acid. The resulting mixture is allowed to stand 5 hours, then diluted with water and extracted with methylene chloride. The organic extracts are washed with water, dried over magnesium sulfate, filtered, and evaporated to a' residue which is crystallized from methanol to give 9u-fluoro-16a-methyl-17ot-ethinyl- 1,4-androstadiene- 175-01-3 ,1 l-dione.

Alternatively, the 9afluoro-l l-keto-diene of this example is also prepared from 9a-fluoro-l6a-methyl-l7aethinyl-4-androstene-1778-01-3,ll-dione by microbiological dehydrogenation with Corynebacterium simplex by procedares analogous to those described in US. Patent No. 2,837,464. The 9m-fiuoro-1l-keto-4-androstene starting compound is prepared by subjecting the 9ot-flu0rO-1lhydroxy-4-androstene of Example 9 to chromic anhydride oxidation as described above.

Similarly, the other halohydrins, prepared as described heretofore, are convertible into the corresponding 9a-haloll-keto-analogs by chromic anhydride oxidation. Thus, one is able to prepare 9u-chloro-16a-methyl-(or 1613- methyl)-17a-ethinyl-4-androstene-17,8-ol-3,11 dione, the corresponding 1,4diene and the analogous 9a-bromo compounds.

EXAMPLE 15 loa-n-butyl-l 7a-ethinyl-4-andr0stene-1 7,8-0l-3,11-dione A. 'I6m-n-butyl-4-androstene-3,11,17 trione. 16ambutylcortisone is oxidized with sodium bismuthate in the manner described in Example 2A to give l6a-n-butyl-4- androstene-3,l 1,17-trione.

B. 16v. n butyl-l 7u-ethinyl-4-andr0stene-17;3-ol-3,11- dione.--The l6a-n-butyl androstene of Example 15A is reacted with acetylene in the manner of Example 28 to yield lGa-n-butyl-l7a-ethinyl-4-androstene-17 3 ol 3,11- dione.

EXAMPLE l6 IGfl-n-butylcortisone is oxidized with sodium bismuthate according to the procedure of Example 15A to give 16p-nbutyl-4-androstene-3,11,17-trione which is then reacted with acetylene in the manner of Example 15B to give n-butyll7a-ethinyl-4-androstene-175-01-3 ,1 l-dione.

EXAMPLE l7 1 6541411411 114 7athinyl-1 ,4-tmdr0stadiene-J 75- ol-3,1 1 -dione The l6p-n-butyl-4-androstene of Example 16 is subjected to the action of Corynebaczerium: simplex according to procedures analogous to US. Patent No. 2,837,464 to give 16fi-n-butyl-l7a-ethinyl-1,4-androstadiene 17 8 ol- 3,1l-dione.

Alternatively, the 165-n-butyl-1,4-androstadiene of this example may be obtained by subjecting l6B-n-butylcoritsone to the action of Corynebaczerium simplex to ob tain 165-n-butylprednisone which, in turn, is oxidized with sodium bismuthate to the l6,3-n-butyl-1,4-androstadiene- 3,11,17-trione. This trione is then reacted with acetylene in the manner of Example 16 to give 16f3-n-butyl-l7aethinyl- 1,4-androstadiene- 17 8-01-3 ,1 l-dione.

EXAMPLE 18 16a-n-butyl-1 7a-ethinyl-1,4-androstadiene-l7fi3- 01-3 ,1 1 -di0ne EXAMPLE l9 1 6 methyl-1 7 a-ethinyI-QBJ 1 18-oxido-4 -andr0stene- 16a-ethylhydrocortisone 2l-acetate is subjected to the reaction sequence described in Example 1 to obtain 16aethyl 17oz ethinyl-9fi,l1fi-oxido-4-androstene-175-01-3- one.

In similar fashion, the 16/8-ethyl epimer of the compound of this example may be prepared from 16,8-ethylhydrocortisone '21-acetate which, in turn, is prepared from 16g8-cortisone-3 ,20bis-semicarbazone in the manner described in copending application, Serial No. 733,843 of Rausser et, al., filed May 8, 19 58.

9 EXAMPLE 20 EXAMPLE 21 9oc-flu0r0-16a-ethyl-17u-elhinyl-4-androstene-11,8,1 7pdiol-3-one 16a ethyl-17a-ethinyl-9p,llfl-oxido-4-androstene-17flol-3-one, prepared as in Example 19, is reacted with hydrogen fluoride in the manner of Example 8 to give 90: fluoro 1Goa-ethyl-17a-ethinyl-4-androstene-11,9,17,3- diol-3-one.

In similar fashion, the l6fi-epimer of the compound of this example may be prepared from l6 8-ethy l-l7aethinyl-9/3,1 1 p-oxido-4-androstene-17B-ol-3-one.

EXAMPLE 22 Qu-fluoro-l6a-ethyl-17a-ethinyl-1,4-andr0stadiene- 115,1 7 3-diol-3-one In the manner of Example 21, l6a-ethyl-l7a-ethinyl- 9,8,115-Oxido-1,4-androstadiene-17B-ol-3-one, is reacted with hydrogen fluoride to give 9a-fluoro-16a-ethyl-l7aethinyl-1,4-androstadiene-1 1,9,17,3-diol-3-one.

Alternatively, the compound of this example may be obtained by subjecting the 9a-fluoro-16a-ethyl-4-androstene of Example 21 to the action of Corynebacterium simplex in the manner described in U.S. Patent -No. 2,837,464.

In similar fashion, the l6fl-ethyl epimer of the compound of this example may be obtained from 16,8-ethyl- 17a ethinyl 9,3,1lfi-oxido-1,4-androstadiene l7p-ol-3- one and hydrogen fluoride.

By methods analogous to those described in above Examples 21 and 22, the 9a-bromo and 9a-chloro analogs of the compounds of the aforementioned examples may be obtained by substituting hydrobromic acid or hydrochloric acid respectively, for hydrofluoric acid in the described procedures.

EXAMPLE 2s 9a fluoro-lfia-ethyl-l7u-ethinyl-4-androstene-115,17,8- diol-3-one is oxidized with chromium trioxide in acetic acid in the manner of Example 14 to give 9wfll1010- 16a-ethyl-17a-ethinyl-4-androstene-17fi-ol-3,1 l-dione.

EXAMPLE 24 The 9a-fluoro-16a-ethyl-4-androstene of Example 23 is subjected to the action of Corynebacterium simplex in the manner described in U.S. Patent No. 2,837,464 to give 90: fluoro-16a-ethyl-17a-ethinyl-1,4 androstadienel7,B-ol-3,l l-dione.

Alternatively, the compound of this example may be prepared by oxidizing 9a-fluoro-16a-ethy -17rx-ethinyl-1,4,- androstadiene 115,175- diol-3-one with chromic anhydride in the manner described in Example 14.

EXAMPLE 25 16a-methyl-1 7u-(1-pr0pinyl) -9fi,1 1,Bxid0-4- androsten e-] 7 -01-3 -one 3 pyrrolidino 9,8,1LB-oxido-16a-methyl-3,5-androstadiene-17-one (the compound of Example IE) is reacted 10 with l-propyne by a procedure analogous to Example 16 to give 16a-methyl-17u-( 1-propinyl)-9,B,1lfi-oxido- 4-androstene-17,8-01-3-one.

In a similar fashion, 3-pyrrolidino-9B,1lp-oxido-l6 3- methyl-3,5-androstadiene-l7-one, prepared as in Example 1F, is converted to l6 8-methyl-l7a-(l-propiny1)-9/3, 1 lp-oxido-4-androstene-17,8-ol-3-one.

EXAMPLE 26 In the manner of Example 5, 3-pyrrolidino-9,B,11,8- oxido-l6a-methyl-1,3,5-androstatriene-17-one (compound of Example SP) is reacted with l-propyne to give 16amethyl (l-propinyl) 9fl,llfl-oxido-l,4-androst-adiene-17fi-ol-3-one.

Alternatively, the 1Got-methyl-17ot-propinyl-androstadiene of this example may be prepared from the corresponding 16a-methyl-17a-propinyl-4-androstene of Example 25 by the action of Corynebacterium simplex according to procedures in U.S. Patent No. 2,837,464.

Similarly, the 16B-methyl epimer of the compound of this example may be prepared from 3-pyrrolidino-9}9,- 11,9 oxido-l6fl-methyl-1,3,5-androstatriene-17-one (prepared as in Example SE) to 'give 16fi-methyl-17u-(1-propinyl) 9 8,1lB-oxido-l,4-androstadiene-l7fi-ol-3-one, or by the microbiological action of Corynebacterium simplex on the corresponding 16,8-methyl-17a-(1-propinyl)- 4-androstene.

By procedures analogous to those described in Examples 25 and 26, the 3-pyrrolidino-3,S-androstadiene of Example 1F and the 3-pyrrolidino-1,3,5-androstatriene of Example 5F may be reacted with homologs of acetylene such as for example, l-butyne, l-pentyne, l-hexyne, and 1-butyne-3-methyl to obtain the 17a(1-butinyl)-, l7a-(l pentinyl)-, 17a-(1-hexinyl)- and 17a-(1-bUti1'1Y1-3- methyl)- analogs of the 93,11,8-oxido compounds of Examples 25 and 26. v

EXAMPLE 2 7 16oz-methyl-17a-(1-pr0pinyl) -4-andr0stene-175-0l- 3,11-di0ne 16a-methyl4-androstene-3,11,17-trione, prepared as in Example 4, is reacted with l-propyne by the procedure analogous to Example 16 to give 16a-methyl-17a-(1- propinyl -4-androstene* 17 8-01-3, l l-dione.

In like manner, the 16B-methyl epimer of the compound of this example may be prepared from 16B-methyl- 4-androstene-3,11,17-trione and l-propyne.

EXAMPLE 28 16a-methyl-17a-(1-pr0pinyl)-1,4-andr0stadiene- 1 713-016,] 1 -di0ne EXAMPLE 29 In the manner described in Example 8, the 913,115- oxido-l6a-methyl-4-androstene of Example 27 is reacted with hydrogen fluoride to give 9afluoro-l6wmethyl-l7u- 1-propinyl)-4-androstene-1 1,9,17fi-diol-3-one.

In a similar manner, the 9u-bromo and Qua-ChlGrO analogs of the compound of this example are prepared by substituting hydrohromic and hydrochloric acid, respectively, for hydrofluoric acid in the above procedure.

The l6fi-methyl epimer of the compounds of this example are prepared from the corresponding 16fi-methyl- 9fl,llB-oxid0-4-androstene and a hydrogen halide.

EXAMPLE 30 We claim: I. Androstenes having the formula:

CH: 3 (m CECE H| i Y' lower alkyl 0% g I Q wherein R is lower allcyl.

2. A 90a-X-16-1OW61' alkyl-17at-ethinyl-4androstene- 175-01-3, ll-dione wherein X is a halogen of atomic weight less than 100.

3. Androstenes having the formula:

- lower alkyl wherein X is a halogen of atomic weight less than 100; and R is lower alkyl.

4. Andros'tenes having the formula:

wherein X is a halogen of atomic weight less than 100; 15 and R is lower alkyl.

5. Androstenes having the formula:

wherein X is halogen; Y is a member of the group consisting of O and (H, 50H); and R is lower alkyl. 6. Androstenes having the following formula:

OH ogen f) loweralkyl CHs/ 1 I wherein R is lower alkyl.

References Cited in the file of thispatent UNITED STATES PATENTS Julian et al Mar. 11, 1952 2,793,217 Muller May 21, 1957 2,816,121 Gould et a1 "Dec. 10, 1957 2,837,464 Nobile June 3, 1958 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3 010 959 November 28 1961 Eugene Pa Oliveto et all,

It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 1, lines 17 to 26 the structural formula should appear as shown below instead of as in the patent:

column ll line 38 for "90 -=X" read 9a=-X- Signed andsealed this 24th day of April 19 2 (SEAL) Attest:

ESTON e6 JOHNSON DAVID LADD Attesting Officer Commissioner of Patents 

5. ANDROSTENES HAVING THE FORMULA:
 6. ANDROSTENES HAVING THE FOLLOWING FORMULA: 